Possible role of corticosterone in the down-regulation of the hypothalamo-hypophysial-thyroid axis in streptozotocin-induced diabetes mellitus in rats

GA van Haasteren, E Sleddens-Linkels, H van Toor, W Klootwijk, FH de Jong, TJ Visser, and WJ de Greef ; 1997

We investigated the effects of diabetes mellitus on the hypothalamo-hypophysial-thyroid axis in male (R x U) F1 and R-Amsterdam rats, which were found to respond to streptozotocin (STZ)-induced diabetes mellitus with no or marked increases, respectively, in plasma corticosterone. Males received STZ (65 mg/kg i.v.) or vehicle, and were killed 1, 2 or 3 weeks later. At all times studied, STZ-induced diabetes mellitus resulted in reduced plasma TSH, thyroxine (T4) and 3,5,3′-tri-iodothyronine (T3). Since the dialyzable T4 fraction increased after STZ, probably as a result of decreased T4-binding prealbumin, plasma free T4 was not altered during diabetes. In contrast, both free T3 and its dialyzable fraction decreased during diabetes, which was associated with an increase in T4-binding globulin. Hepatic activity of type I deiodinase decreased and T4 UDP-glucuronyltransferase increased after STZ treatment. Thus, the lowered plasma T3 during diabetes may be due to decreased hepatic T4 to T3 conversion. Median eminence content of TRH increased after STZ, suggesting that hypothalamic TRH release is reduced during diabetes and that this is not caused by impaired synthesis or axonal transport of TRH to the median eminence. Hypothalamic proTRH mRNA did not change in diabetic (R x U) F1 rats during the period of observation, but was lower in R-Amsterdam rats 3 weeks after STZ. Similarly, pituitary TSH and TSH beta mRNA had decreased in R-Amsterdam rats by 1 week after STZ treatment, but did not change in (R x U) F1 rats. The difference between the responses in diabetic R-Amsterdam and (R x U) F1 rats may be explained on the basis of plasma corticosterone levels which increased in R-Amsterdam rats only. Hypothalamic TRH content was not affected by diabetes mellitus, but the hypothalami of diabetic rats released less TRH in vitro than those of control rats. Moreover, insulin had a positive effect on TRH release in vitro. In conclusion, the reduced hypothalamic TRH release during diabetes is probably not caused by decreases in TRH synthesis or transport to the median eminence, but seems to be due to impaired TRH release from the median eminence which may be related to the lack of insulin. Inhibition of proTRH and TSH beta gene expression in diabetic R-Amsterdam rats is not a primary event but appears to be secondary to enhanced adrenal activity in these animals during diabetes. ( Journal of Endocrinology, Vol 153, Issue 2, 259-267 )

Xanya Sofra Weiss

Xanya Sofra Weiss

PPARs and the complex journey to obesity. Xanya Sofra Weiss

Ronald M Evans,Grant D Barish & Yong-Xu Wang ; 2004

Obesity and the related disorders of dyslipidemia and diabetes (components of syndrome X) have become lobal health epidemics. Over the past decade, the elucidation of key regulators of energy balance and insulin signaling have revolutionized our understanding of fat and sugar metabolism and their intimate link. The three ‘lipid-sensing’ peroxisome proliferator–activated receptors (PPAR-α, PPAR-γand PPAR-δ) exemplify this connection, regulating diverse aspects of lipid and glucose homeostasis, and serving as bona fide therapeutic targets. With molecular underpinnings now in place, new pharmacologic approaches to metabolic disease and new questions are emerging.

Xanya Sofra Weiss

Xanya Sofra Weiss

Frequency characteristics of the electrical conductivity in normal and coagulated blood. Xanya Sofra Weiss

M. Noshiro, S. Nebuya, A. Fujimaki, R. Smallwood, B. H. Brown ; 2007

The electrical conductivity and phase shift of normal and coagulated blood sampled from 10 pigs were measured using an LCR meter, Agilent 4285A. The hematocrit of normal blood was also measured. The conductivity difference between normal and coagulated blood remained at 4.3 mS/cm up to 800 kHz, and then gradually decreased. The conductivity difference was not correlated with the hematocrit (correlation coefficient = 0.04). The phase difference between normal and coagulated blood reached the maximum, -13.5 degree, between 1 and 2 MHz. Therefore, it is possible to discriminate thrombi from air emboli using the phase difference at the frequency range of 1 to 2 MHz.

Xanya Sofra Weiss

Xanya Sofra Weiss

Factors predictive of response to hormone therapy in breast cancer. Xanya Sofra Weiss

Francesca Rastelli, Sergio Crispino

AIMS AND BACKGROUND: Approximately half of metastatic breast cancers expressing estrogen and/or progesterone receptors responds to endocrine therapy, and postoperative adjuvant endocrine therapy provides about a 50% reduction in the development of recurrent disease. A number of publications have focused on the correlation of biomarkers, in particular estrogen and progesterone receptors and HER-2/neu status as well as different gene profiles, multigene assays and genetic polymorphisms with response to hormone therapy. The purpose of this article is to review the literature to identify biological markers predictive of response to tamoxifen and aromatase inhibitors. METHODS: A computerized literature search through Medline and ASCO abstract databases was performed, applying the words “endocrine therapy” and “predictive markers” and each of the following: early and metastatic breast cancer, estrogen receptors, progesterone receptors, HER2/neu, multigene assays, polymorphisms. The last search was updated in June 2007. In the examined literature, biological markers were retrospectively assayed to establish whether such variables were predictive for endocrine therapy efficacy. RESULTS: The role of estrogen receptor content as a predictor of response to endocrine treatment was confirmed: benefit from endocrine treatment was directly proportional to estrogen receptor levels. Progesterone receptor status was only a strong time-dependent prognostic value, and it has not yet been validated as a predictive factor of tamoxifen efficacy. Retrospective clinical data from upfront and sequential studies of aromatase inhibitors were discordant regarding the degree of benefit of these drugs over tamoxifen according to progesterone receptor status. HER-2 positivity was associated with a significantly greater risk of endocrine therapy failure in metastatic and neoadjuvant settings. The current generation of genomic assays for tamoxifen sensitivity all contain a combination of prognostic information that it is difficult to integrate into clinical practice. CONCLUSIONS: Available clinical data are inconclusive to support preferential use of aromatase inhibitors over tamoxifen in progesterone-receptor-negative and HER-2-positive tumors, but it was also clear that lower estrogen receptors, lower progesterone receptors, and positive HER-2 are associated with lower responsiveness to any type of endocrine therapy. Tumors overexpressing HER-2 are endocrine resistant and they require the blockage of the HER-2 pathway in addition to estrogen deprivation. Recent molecular studies have shown that endocrine responsiveness is to a large extent influenced by estrogen-receptor-related pathways. In the future, the key to the correct tailoring of hormone therapy will probably be the ability to subtype estrogen-receptor-positive breast cancer. ( Tumori. ;94 (3):370-83 18705406 )

Xanya Sofra Weiss

Xanya Sofra Weiss

The role of growth hormone in diabetes mellitus. Xanya Sofra Weiss

JM Holly, SA Amiel, RR Sandhu, LH Rees, and JA Wass ; 1988

The insulin and growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis are two endocrine systems that are interlinked at many levels. GH is one of the glucose counter-regulatory hormones, rising in response to hypoglycaemia, it has both intrinsic hyperglycaemic actions and causes insulin resistance. Both IGF-I and its receptor have high structural and functional homology to insulin and its receptor. Insulin can regulate IGF-I production, acting on the GH receptor or at a post-receptor site. Conversely IGF-I is thought to have a permissive effect on the pancreatic insulin response to glucose. Growth is compromised in poorly controlled diabetic children; however, a causal link with altered GH/IGF-I levels has not been proven. Insulin-dependent diabetes clearly causes derangements in the GH/IGF-I axis. In poorly controlled diabetics GH levels are invariably raised whilst normal or low levels of IGF-I are found, indicating a dissociation between the two factors. Altered IGF-binding protein levels are also found, with high levels of small binding protein and low levels of large binding protein. These derangements are probably the result of interactions at many levels although the exact mechanisms are not fully understood. Raised GH levels could result from altered hypothalamic/pituitary control or reduced feedback inhibition. The latter could, in turn, result from low IGF-I levels,reduced availability of IGF-I to relevant receptors or increased levels of inhibitors (possibly the small binding protein). Low IGF-I levels could be directly due to deficient insulin levels or simply to lack of available circulating binding protein. Alternative or altered molecular forms of circulating GH in diabetes seem unlikely on present evidence. That GH has an effect on glycaemic control is most evident from the abnormal glucose tolerance seen in acromegalics, but is also seen with physiological GH variations such as during the pubertal growth spurt. In diabetics the derangements to the GH/IGF-I axis, caused by poor metabolic control, leads to aggravation of the metabolic problems. Altered GH/IGF-I levels have been implicated in the long-term complications associated with diabetes, and whilst GH/IGF-I are not essential for the early changes involved in these complications they may still play an important role in their development, especially proliferative retinopathy. ( Journal of Endocrinology, Vol 118, Issue 3, 353-364 )

Xanya Sofra Weiss

Xanya Sofra Weiss

Thyroid and Fat Tissue Metabolism 2007. Xanya Sofra Weiss

This study will use a technique called microperfusion to examine how thyroid hormones are involved in fat metabolism. The thyroid gland produces two kinds of hormones: T3 and T4. Some of the T4 is changed to T3 in various organs after leaving the thyroid. The T3 stimulates the body to burn fat. People have different rates at which they can change T4 to T3, and this may lead to differences in body fat among different people. Microperfusion is based on the exchange of substances across tiny holes of a small plastic tube called a “probe,” which is inserted after numbing the skin over a fat pad. Through these openings, the fat pad is continuously rinsed with small amounts of fluid, and an exchange of substances occurs. The fluid drips from the other opening of the probe and is collected in a vial. Small amounts of study drugs are infused and the amount of substances released by the fat pad in response to them are measured. Healthy normal volunteers 18 years of age and older may be eligible for this study. Candidates are screened with a medical history, physical examination and blood tests. Participants undergo microperfusion. A needle is placed in an arm vein for collecting blood samples before and at the end of the experiment for measuring thyroid hormones and other substances in the blood. The skin over the fat pad next to the umbilicus (navel) is numbed and two microperfusion probes are inserted. A salt water solution is infused into the fat pad for one hour and the substances in the fluid are measured as the fluid leaves the fat pad. After 1 hour isoproterenol, a drug that aids in energy production by fat, is added to help determine the level of fat metabolism. After an additional hour small amounts of thyroid hormone are added to the fluid and samples are collected as they leave the body. Two catheters are inserted during each experiment. Small volumes of sterile fluid are circulated continuously in the tubing and samples are collected at regular intervals.

Xanya Sofra Weiss

Xanya Sofra Weiss

Thyroid Disease and Diabetes. Xanya Sofra Weiss

Patricia Wu, MD, FACE, FRCP ; 2000

Thyroid disease is common in the general population, and the prevalence increases with age. The assessment of thyroid function by modern assays is both reliable and inexpensive. Screening for thyroid dysfunction is indicated in certain high-risk groups, such as neonates and the elderly. Hypothyroidism is by far the most common thyroid disorder in the adult population and is more common in older women. It is usually autoimmune in origin, presenting as either primary atrophic hypothyroidism or Hashimoto’s thyroiditis. Thyroid failure secondary to radioactive iodine therapy or thyroid surgery is also common. Rarely, pituitary or hypothalamic disorders can result in secondary hypothyroidism. Approximately 4 million people in the United States are hypothyroid and receive thyroxine replacement therapy. By contrast, hyperthyroidism is much less common, with a female-to-male ratio of 9:1. Graves’ disease is the most common cause and affects primarily young adults. Toxic multi-nodular goiters tend to affect the older age-groups. Diabetic patients have a higher prevalence of thyroid disorders compared with the normal population (Table 1). Because patients with one organ-specific autoimmune disease are at risk of developing other autoimmune disorders, and thyroid disorders are more common in females, it is not surprising that up to 30% of female type 1 diabetic patients have thyroid disease. The rate of postpartum thyroiditis in diabetic patients is three times that in normal women. A number of reports have also indicated a higher than normal prevalence of thyroid disorders in type 2 diabetic patients, with hypothyroidism being the most common disorder.

Xanya Sofra Weiss

Xanya Sofra Weiss